We propose to establish an Autoimmunity Center of Excellence at Yale University that will serve the southern New England region. Three clinical areas are involved: Rheumatic diseases (primary Sj"gren's syndrome (pSS)), Type 1 diabetes (T1DM), and inflammatory bowel disease (IBD). The Research Component includes 2 projects. The first, builds on a history of investigations of TNF family mediators in autoimmune and inflammatory diseases at Yale, and will analyze tertiary lymphoid organs from patients with pSS and the role of the IL-23/Th17 and IL-12/IFN-g pathways. The number and function of regulatory T cells will be studied. The second project is an analysis of autoreactive B cells in T1DM and in patients with T1DM treated with anti-CD20 mAb, in patients with pSS, and in patients with IBD. A pilot study is proposed in which new technologies will be developed to visualize lymphocytes in vivo and humanized mice as a prelude to clinical investigations. An administrative and sample management core will provide regulatory and administrative support and central processing and storage of samples. The Clinical component involves investigators at the Yale New Haven Hospital and other regional instutions including Long Island, Bridgeport Hospital, and St. Francis Hospital. Two Clinical trial concepts are proposed: A Phase I trial of a fusion protein containing autoantigenic epitopes for treatment of patients with Type 1 diabetes, and a Phase II trial of antip40 mAb CNTO 1275 (Ustekinumab) for treatment of pSS. Dr. Insoo Kang will be the Research Representative and Dr. Kevan Herold will be the Clinical Representative. The Center is an integrated basic and clinical research program based on the study of mechanisms that are common to the different autoimmune disease states. Clinical samples from patients will be analyzed as part of the basic science components, and the studies in the basic projects have direct impact on the understanding and the analysis of clinical protocols. Samples from both clinical trials will be analyzed and are fully integrated into the studies that are described in the Research component. The Center fulfills the goal of "translational" research moving between laboratory and clinic to understand human disease and develop new therapies. Autoimmune diseases are among the most common diseases in the US. The premise of this Center is that understanding the mechanisms that underly the progression of disease can lead to new treatments. The Yale Autoimmunity Center of Excellence involves an integration of basic and clinical scientists for the study and treatment of 3 clinical diseases: primary Sj"gren's syndrome, Type 1 diabetes, and inflammatory bowel disease Clinical Component: Clinical Component of Yale Autoimmunity Center of Excellence (Herold, K) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The Clinical component of the Yale Autoimmunity Center of Excellence involves physicians in the fields of Endocrinology, Rheumatology, and Gastroenterology. The physicians are from the southern New England region, an area that has a population of 6 million people. There are 3 areas of focus of the Center: Rheumatologic diseases (primary Sj"gren's Syndrome), Type 1 diabetes, and Inflammatory Bowel disease. The clinical sites involved are Yale New Haven Hospital, Bridgeport Hospital, St. Francis Hospital, and a large gastroenterology practice on Long Island. All of the clinical investigators have extensive experience in conducting clinical studies and in many cases have been the principle investigator on NIH clinical trials as well as industry trials. The ACE will make use of the resources of the Clinical and Translational Science Award at Yale, such as trial coordinators, statistical and regulatory support, and the in and outpatient facilities where study subjects are seen and treated. Two clinical trials are proposed based on preclinical and mechanistic studies. The first is a Phase I trial of immunization of patients with Type 1 diabetes with a fusion molecule containing antigen epitopes thought to be involved in the disease. In preclinical studies in the NOD mouse, immunization with a similar fusion molecule attenuated spontaneous disease, disease induced with cyclophosphamide, and the adoptive transfer of disease. The primary endpoint of this trial is safety but mechanistic studies will be done to determine the actions of the immunization. The second trial is a Phase II trial of the anti-p40 mAb CNTO 1275 (Ustekinumab) for treatment of primary Sj"gren's syndrome. This trial is designed to establish whether the drug, which targets the IL-12 and IL-23 pathways, has an effect on the histologic findings of the disease. Lip biopsy samples will be analyzed for structure of tertiary lymphoid organs and their cellular content. A central sample management core will collect and process all samples and maintain an inventory of frozen cells and tissues. A key aspect of the Center is the integration of clinical investigators with the basic research scientists by virtue of the positioning of clinical and laboratory investigators in both basic and clinical divisions and the integrative studies applied to clinical investigation. Autoimmune diseases are among the most common diseases in the United States. The Clinical Component of the Yale Autoimmunity Center of Excellence will provide an integrative approach to develop new treatments for autoimmune diseases. Three clinical areas are the focus of the proposal - Rheumatologic diseases (primary Sj"gren's syndrome, Type 1 diabetes, and inflammatory bowel disease. The studies in this Center will evaluate new treatments and suggest future approaches that may be integrated into practice